A new Australian study is set to give hope to young people diagnosed with sarcomas, finding that a targeted therapy called tyrosine kinase inhibitors could benefit more patients than previously realised, and effectively opening up a new treatment option for some of those who need it most.
Published this week in Molecular Cancer Therapeutics, and involving collaboration between Children's Cancer Institute, UNSW Sydney, Monash University and Queensland Children’s Hospital, the study has important implications for the treatment of sarcomas, which tend to grow aggressively in young people and can be extremely difficult to treat.
"We are very excited with these results, which took years of dedicated work, and which show how laboratory research can truly help make a difference in the clinic," said Dr Emmy Fleuren, Team Leader, Sarcoma Biology and Therapeutics, Children's Cancer Institute, who led the research and was corresponding author on the publication.
While tyrosine kinase inhibitors have previously been shown to be beneficial for certain sarcoma patients, a major obstacle to using these more broadly has been a lack of predictive response biomarkers — markers that clinicians can use to identify which patients are most likely to respond and to guide treatment.
"Childhood sarcomas usually lack genetic mutations that doctors can use to select a targeted drug for their patients," explained Dr Fleuren. "Now, we have shown that advanced laboratory techniques can reveal drug-sensitive tumours even when typical genetic mutations are absent."
For the study, the researchers analysed samples from 107 children with sarcoma enrolled on the Zero Childhood Cancer Program (ZERO) — Australia’s precision medicine program for children with cancer, jointly led by Children’s Cancer Institute and the Kids Cancer Centre at Sydney Children’s Hospital, Randwick — representing one of the largest and most diverse cohorts of high-risk young sarcoma patients investigated to date.
Using genomic and transcriptomic sequencing of the children’s tumours, coupled to phosphoproteomics, the researchers found that although specific genetic alterations driving sarcoma growth are rare, when present they are ‘therapeutically actionable’ – meaning they can be targeted for treatment. The researchers also showed that in certain contexts, sensitivity to tyrosine kinase inhibitors can be predicted by analysing RNA expression.
A key finding was that certain types of a tyrosine kinase inhibitor called FGFR-inhibitors were effective against a very poor-prognosis sarcoma which forms in muscle tissue, known as PAX3-FOXO1 fusion-positive rhabdomyosarcoma, or FP-RMS.
In mice growing FP-RMS tumours derived from children, roblitinib (an FGFR4-specific inhibitor), and lenvatinib (a multi-tyrosine kinase inhibitor) each significantly inhibited tumour growth. Most excitingly, in a patient with relapsed metastatic FP-RMS, the therapy resulted in a clear clinical response, with their tumour shrinking over several months.
"This is the first time that FGFR4-kinase inhibitors have been found to be effective against this particular type of cancer in living models and in a patient, so these results are very exciting," said Dr Fleuren.
Further investigations showed that, in order to be sensitive to these drugs, tumours must have co-expression of the tyrosine kinase FGFR4 and its ligand FGF8. Encouragingly, examination of international sarcoma datasets showed this RNA co-expression signature to be a recurring feature in FP-RMS tumours, suggesting that many more young sarcoma patients might benefit from this therapy.
"As Australia’s only research laboratory solely dedicated to studying childhood sarcomas, we are determined to find new ways to treat these cancers and help more children," said Dr Fleuren. "With these results, we have shown that we can generate compelling preclinical evidence and successfully translate our research discoveries to the clinic."
"As a direct result of our work, a tyrosine kinase inhibitor is now prospectively suggested as an option for high-risk FP-RMS patients enrolled on ZERO who have exhausted other treatment options. We now want to expand on our success and discover more ways to match targeted therapies to young sarcoma patients who are currently still missing out."
This research was primarily funded by Cancer Institute NSW, with pilot research support from Can Too Foundation and additional contributions from The Kids’ Cancer Project.
